US9650380B2ActiveUtilityA1
Difluoromethylene compound
Est. expiryJul 27, 2032(~6.1 yrs left)· nominal 20-yr term from priority
Inventors:Keita NagaiMotoaki BabaShinichi FujiokaKoh NagasawaHirobumi TakahashiEri KondohSachie SogoKenichi TanakaYoshiki Itoh
A61P 9/10C07D 231/56C07D 471/04C07D 401/14C07D 409/06C07D 209/08C07D 403/06C07D 401/06C07D 413/06A61K 31/416A61P 19/02A61K 31/404A61P 19/06A61P 13/04A61P 13/12
42
PatentIndex Score
0
Cited by
85
References
18
Claims
Abstract
A compound having an URAT1 inhibitory activity, and an URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition containing the compound. More specifically, a compound represented by the formula (I): wherein R 1 is -Q 1 -A 1 or the like; R 2 is a hydrogen atom, a halogen atom, a lower alkyl group or the like; W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom or a methine group optionally having substituents, or the like; X and Y are each a single bond, an oxygen atom or the like; Z is a hydroxyl group or COOR 3 or the like.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A method for producing a compound of the formula (I-6):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s); and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the steps of:
(1) reacting a compound of the formula (III):
[wherein R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and X L is a halogen atom or a trifluoromethanesulfonyloxy group]
with a compound of the formula (IV):
R 1 -LG (IV)
[wherein R 1 is as defined above; and LG is a leaving group]
to obtain a compound of the formula (V):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 , W 4 and X L are as defined above];
(2) reacting the compound of the formula (V) with an organic zinc compound to obtain a compound of the formula (IX):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and PG 2 is a protective group];
(3) reacting the compound of the formula (IX) with a fluorinating agent to obtain a compound of the formula (II-2):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 , W 4 and PG 2 are as defined above]; and
(4) removing the protective group PG 2 of the compound of the formula (II-2).
2. A method for producing a compound of the formula (I-6):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s); and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the steps of:
(1) reacting a compound of the formula (V)
[wherein R 1 , R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and X L is a halogen atom or a trifluoromethanesulfonyloxy group]
with an organic zinc compound to obtain a compound of the formula (IX):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and PG 2 is a protective group];
(2) reacting the compound of the formula (IX) with a fluorinating agent to obtain a compound of the formula (II-2):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 , W 4 and PG 2 are as defined above]; and
(3) removing the protective group PG 2 of the compound of the formula (II-2).
3. A method for producing a compound of the formula (I-6):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s); and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the steps of:
(1) reacting a compound of the formula (IX):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and PG 2 is a protective group]
with a fluorinating agent to obtain a compound of the formula (II-2):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 , W 4 and PG 2 are as defined above]; and
(2) removing the protective group PG 2 of the compound of the formula (II-2).
4. A method for producing a compound of the formula (I-6):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s); and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the step of:
(1) removing a protective group PG 2 of a compound of the formula (II-2):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and PG 2 is a protective group].
5. A method for producing a compound of the formula (V):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s);
X L is a halogen atom or a trifluoromethanesulfonyloxy group; and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the step of:
(1) reacting a compound of the formula (III):
[wherein R 2 , W 1 , W 2 , W 3 , W 4 and X L are as defined above]
with a compound of the formula (IV):
R 1 -LG (IV)
[wherein R 1 is as defined above; and LG is a leaving group].
6. A method for producing a compound of the formula (IX):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s);
PG 2 is a protective group; and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the step of:
(1) reacting a compound of the formula (V):
[wherein R 1 , R 2 , W 1 , W 2 , W 3 and W 4 are as defined above; and X L is a halogen atom or a trifluoromethanesulfonyloxy group]
with an organic zinc compound.
7. A method for producing a compound of the formula (II-2):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s);
PG 2 is a protective group; and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the step of:
(1) reacting a compound of the formula (IX)
[wherein R 1 , R 2 , W 1 , W 2 , W 3 , W 4 and PG 2 are as defined above]
with a fluorinating agent.
8. A method for producing a compound of the formula (XII):
[wherein
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s);
PG 2 is a protective group; and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the step of:
(1) removing a protective group PG 1 of a compound of the formula (XI):
[wherein R 2 , W 1 , W 2 , W 3 , W 4 and PG 2 are as defined above; and PG is a protective group].
9. A method for producing a compound of the formula (II-2):
[wherein
R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, a cycloalkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group or a group represented by the general formula: -Q 1 -A 1 ;
Q 1 represents a single bond or a lower alkylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with a carbonyl group, a sulfinyl group or a sulfonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by lower alkyl group(s));
A 1 represents an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from the following <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s);
PG 2 is a protective group; and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group];
wherein the method comprises the step of:
(1) reacting a compound of the formula (XII):
[wherein R 2 , W 1 , W 2 , W 3 , W 4 and PG 2 are as defined above]
with a compound of the formula (IV):
R 1 -LG (IV)
[wherein R 1 is as defined above; and LG is a leaving group].
10. The method according to any one of claims 1 to 4 and 6 to 9 , wherein PG 2 is selected from the group consisting of a lower alkyl group, a halo lower alkyl group, a lower alkenyl group and an aralkyl group.
11. The method according to any one of claims 1 to 7 and 9 , wherein R 1 is a group represented by the general formula: -Q 1 -A 1 .
12. The method according to any one of claims 1 , 2 and 6 , wherein the step of reacting the compound of the formula (V) with the organic zinc compound to obtain the compound of the formula (IX) is carried out in the presence of a palladium catalyst.
13. The method according to claim 12 , wherein the step of reacting the compound of the formula (V) with the organic zinc compound to obtain the compound of the formula (IX) is carried out in the presence of an additional a phosphine ligand.
14. The method according to any one of claims 1 , 2 and 6 , wherein, in the step of reacting the compound of the formula (V) with the organic zinc compound to obtain the compound of the formula (IX), the organic zinc compound is a Reformatsky agent.
15. The method according to any one of claims 1 to 9 , wherein W 3 is a methine group.
16. A compound of the formula (XII):
[wherein
PG 2 is a protective group;
R 2 represents a hydrogen atom, a substituent selected from the following <Substituent group M> or a group represented by the general formula: -Q 2 -A 2 ;
Q 2 represents a single bond, a lower alkylene group or lower alkenylene group (wherein the entirety of each of the 1 or 2 or more methylene group(s) that constitute(s) the lower alkylene group may be independently replaced with an oxygen atom, a nitrogen atom or a carbonyl group, and/or the hydrogen(s) that constitute(s) the methylene group(s) may be substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
A 2 represents a cycloalkyl group, an aliphatic heterocycle group, an aryl group or a heteroaryl group optionally substituted by 1 to 3 substituent(s) selected from <Substituent group L> (wherein the adjacent optional two substituents on the aryl group or heteroaryl group may be together to form a lower alkylenedioxy group);
W 1 , W 2 , W 3 and W 4 are each independently a nitrogen atom, or a methine group optionally having substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group and a halo lower alkoxy group; provided that 0 to 4 of W 1 , W 2 , W 3 and W 4 is/are nitrogen atom(s); and
<Substituent group L> and <Substituent group M> are defined as follows;
<Substituent group L>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, a lower alkoxy carbonylamino group, an aralkyl group, an aryloxy group, a heteroaryloxy group, a lower alkenyl group, and a cyano lower alkyl group
<Substituent group M>:
a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, an amino group, a carboxyl group, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy carbonyl group, a lower alkanoyl group, a lower alkylthio group, a lower alkyl sulfonyl group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a mono-lower alkyl carbamoyl group, a di-lower alkyl carbamoyl group, a lower alkanoyl amino group, a lower alkyl sulfonylamino group, and a lower alkoxycarbonylamino group].
17. The compound according to claim 16 , wherein PG 2 is selected from the group consisting of a lower alkyl group, a halo lower alkyl group, a lower alkenyl group and an aralkyl group.
18. The compound according to any one of claims 16 and 17 , wherein W 3 is a methine group.Cited by (0)
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